1. Field of the Invention
This invention relates to instruments and methods for performing non-invasive measurements of analyte concentrations and for monitoring, analyzing and regulating tissue status, such as tissue glucose levels.
2. Description of the Background
Diabetes is a chronic life threatening disease for which there is presently no cure. It is the fourth leading cause of death by disease in the United States and at least 175 million people worldwide are estimated to be diabetic. Diabetes is a disease in which the body does not properly produce or respond to insulin. The high glucose concentrations that can result from this affliction can cause severe damage to vital organs, such as the heart, eyes and kidneys.
Type I diabetes (juvenile diabetes or insulin-dependent diabetes mellitus) is the most severe form of the disease, comprising approximately 10% of the diabetes cases in the United States. Type I diabetics must receive daily injections of insulin in order to sustain life. Type II diabetes, (adult onset diabetes or non-insulin dependent diabetes mellitus) comprises the other 90% of the diabetes cases. Type II diabetes is often manageable with dietary modifications and physical exercise, but may still require treatment with insulin or other medications. Because the management of glucose to near-normal levels can prevent the onset and the progression of complications of diabetes. Persons afflicted with either form of the disease are instructed to monitor their blood glucose concentration in order to assure that the appropriate level is achieved and maintained.
Traditional methods of monitoring the blood glucose concentration of an individual require that a blood sample be taken. This method can be painful, inconvenient, costly, and pose the risk of infection. Another glucose measuring method involves urine analysis, which, aside from being inconvenient, may not reflect the current status of the patient""s blood glucose because glucose appears in the urine only after a significant period of elevated levels of blood glucose. An additional inconvenience of these traditional methods is that they require testing supplies such as collection receptacles, syringes, glucose measuring devices and test kits. Although disposable supplies have been developed, they are costly and can require special methods for disposal.
Many attempts have been made to develop a painless, non-invasive external device to monitor glucose concentrations. Various approaches have included electrochemical and spectroscopic technologies, such as near-infrared spectroscopy and Raman Spectroscopy. Despite extensive efforts, however, none of these methods has, so far, yielded a non-invasive device or method for the in vivo measurement of glucose that is sufficiently accurate, reliable, convenient and cost-effective for routine use.
The phenomenon of endogenous skin fluorescence, as well as endogenous fluorescence of other biological tissues, has been well documented in the literature. Methods for non-invasively measuring skin fluorescence have been developed and incorporated into commercially available instruments (e.g. Skin Skan or Fluorolog). In skin, important fluorophores include tryptophan-containing proteins, which fluoresces in the 350-450 nm region, and fluorophores associated with collagen cross links, skin oils, NADH, FAD, other flavoproteins, elastin, and quinones, which fluoresce in a broad region from 420 to 650 nm (J. Invest. Dermatol. 111:776-780, 1998, and references therein).
Fluorescence has been used to predict malignancies in tissue, e.g., cervical tissue, bladder tissue, and the buccal cavity. Fluorescence of dyes (fluorescence associated with dyes that selectively bind to biological compounds) has also been used to study in vivo cellular processes.
The invention overcomes problems and disadvantages associated with current strategies and designs and provides new instruments and methods for monitoring, analyzing and regulating in vivo glucose levels or other analyte levels in an individual.
In one general aspect, the invention features a non-invasive glucose monitoring instrument useful in vivo. The instrument comprises a radiation source, a radiation detector and a processing circuit or analyzing means. The radiation source is capable of directing excitation radiation to a portion of a tissue surface of a patient and emits radiation at at least one wavelength that excites a target in the tissue to emit radiation. The tissue surface may be an exterior or an interior tissue surface of a patient. For example, the surface may be a mucosal area, such as the gums or other mucosal area, the eyeballs, and surrounding areas, such as the eyelids. More preferably, the surface is the patient""s skin. Alternately, the tissue surface may be an interior surface such as the serosal or mucosal surface of an organ.
The excited target provides information that can be correlated with the patient""s glucose level. More specifically, the radiation emitted from the excited target and received at the tissue surface correlates with the glucose level of the tissue and thus provides a glucose level indication of the patient. A glucose level indication is a quantitative, qualitative or relative measurement that correlates with the blood glucose content or concentration of the patient.
The radiation detector is positioned to receive the radiation emitted from the tissue surface. Radiation received at the surface may be quenched or amplified by one or more matrix, cellular, or mitochondrial components, or any other cellular component reflective of metabolic activity, in the tissue. A processing circuit is operatively connected to the radiation detector that translates emitted radiation to a measurable signal to obtain the glucose level indication. Alternately, analyzing means is operatively connected to the radiation detector for analyzing radiation detected by the radiation detector and translating the detected radiation to an indication of the tissue glucose level.
The excited target is not glucose itself, but a molecular component of the patient such as, for example, a component of skin or other tissue, that is related, is sensitive to, or co-varies with glucose concentration, such as tryptophan, elastin, collagen or collagen cross links, NADH, or FAD. Suitable targets are structural components, and compounds and molecules that reflect alterations in the environment of matrix, cellular, or mitochondrial components, or any other cellular component reflective of metabolic activity, of the tissue and are sensitive to or correlate with tissue glucose concentration. The target may provide an emitted fluorescence signal that is related to the patient""s blood glucose level, and/or absorb certain portions of the returned signal creating a unique signal correlatable with glucose concentration, or a combination of the two.
The radiation detector is responsive to the emission band of the target or species in the skin. Preferably, the excitation radiation is ultraviolet radiation or visible light, such as blue light. The radiation emitted at the tissue surface is preferably fluorescence radiation from the excitation of the non-glucose target.
The instrument may further include means for measuring scattering re-emitted or scattered radiation remitted from the irradiated skin and means for measuring absorbance, such as absorption from skin chromophores, like oxy- and/or deoxyhemoglobin, and melanin. The radiation emitted, reflected or transmitted from the excited target and signal therefrom correlates with the blood glucose of the patient.
Another embodiment of the invention is directed to a non-invasive analyte monitoring instrument comprising a radiation source for directing excitation radiation to a portion of a tissue surface, (i.e., about 0.5 to 4 square centimeters of skin), a radiation detector, and a processing circuit. Preferably, the analyte being xe2x80x9cdetectedxe2x80x9d maybe correlated with glucose. The radiation source is a visible light source or an ultraviolet light source that emits excitation radiation at least one wavelength that excites a target in the tissue.
The excited target emits radiation that correlates with the analyte level of the tissue or blood. The amount of fluorescence can reflect the quantity of a matrix, cellular or mitochondrial component that is related to the blood glucose level of the blood. The radiation from the excited target and received at the tissue surface may be affected by factors such as absorption, scattering, temperature, quenching, polarization, and remission of fluorescence. As with the previous embodiment, radiation received at the surface may be quenched or amplified by one or more matrix, cellular or mitochondrial components, or any other cellular component reflective of metabolic activity, in the tissue. The radiation detector is positioned to receive radiation emitted from the surface of the tissue. The radiation received at the surface of the tissue provides an indication of the analyte level of the patient. The processing circuit is operatively connected to the radiation detector and translates emitted radiation to a measurable signal to obtain an indication of the analyte concentration or trend in the change of concentration (collectively the analyte level).
Another embodiment is directed to a non-invasive method of detecting a glucose level of a tissue comprising: exciting a non-glucose target in the tissue wherein the target emits radiation such that the radiation received at the tissue surface is indicative of a glucose level of a patient; detecting radiation emitted by the target and transmitted through the intervening tissue to the surface; and determining the glucose level or trend in glucose levels from the radiation detected. In a preferred embodiment, the excitation radiation is ultraviolet or visible light.
Preferred targets for monitoring or detecting glucose are non-glucose molecular species in the skin such as tryptophan-containing proteins or a matrix target, like PDCCL (pepsin digestible collagen cross links) and non-pepsin digestible collagen cross links, elastin, or other matrix and non-matrix tissue components, such as cellular or mitochondrial, NADH, pentosidine, flavoproteins, FAD, and the like. Targets useful for detecting analytes are excited by ultraviolet or visible radiation and act as bioamplifiers or bioreporters. Targets may be structural matrix, cellular, mitochondrial, or other tissue components. Suitable targets reflect alterations within the environment of matrix and/or tissue components of the skin or other tissue with either creation of compounds that fluoresce or causing an extant compound to fluoresce and may act as bioamplifiers or bioreporters when excited with ultraviolet radiation. Alternately, quenchers, absorbers, or scatterers may be what are acting to amplify or report. Other targets may reflect changes in redox rates of analyte transport in the tissue.
Another embodiment is directed to a method for detecting diabetes in a patient comprising: exciting a non-glucose target using ultraviolet or visible radiation wherein the collection of light from the excited target is indicative of a glucose level or state of diabetes of a patient; detecting radiation emitted by the target; determining the glucose level from the radiation detected; and detecting diabetes based on the determined glucose level or other information.
Another embodiment is directed to an instrument for assessing changes in the structural matrix, cellular, or mitochondrial components, or any other cellular component reflective of metabolic activity, of the skin of a patient comprising means for measuring fluorescence emitted from the skin, means for measuring scattering, and means for measuring absorbance. This embodiment may further include means for irradiating the tissue with a plurality of wavelengths of excitation light and means for synchronously scanning the fluorescence emitted from the skin with the excitation light.
Another embodiment is directed to an instrument in which fluorescence measurements of matrix, cellular, or other components are reflective of the onset or state of diabetes.
Another embodiment is directed to a method in which fluorescence measurements of matrix, cellular, or other components is reflective of the onset or state of diabetes.
Another embodiment is directed to an instrument for assessing changes in the environment of the matrix, cellular, or mitochondrial components, or other cellular components reflective of metabolic activity, of the skin or other tissue of a patient comprising: means for measuring fluorescence; means for measuring scattering; and means for measuring absorbance. Preferred embodiments further include means for combining signals from the means for measuring scattering and means for measuring absorbance in visible, UV, or infrared regions with fluorescence measurements.
Still another aspect of the invention relates to a non-invasive method of assessing a change in the superficial structural matrix, cellular, or mitochondrial components, or any other cellular component reflective of metabolic activity, of a tissue, or a change in the environment of matrix, cellular, mitochondrial, or other components reflective of metabolic activity, comprising exposing the tissue to radiation at a first wavelength, detecting fluorescence emitted by exposed tissue, exposing the tissue to radiation of a second wavelength, detecting scattering re-emitted from the exposed tissue, and deriving an indication representative of the change in the structural matrix, cellular or mitochondrial components of the tissue, or a change in tissue matrix, cellular, or mitochondrial components, or other cellular components reflective of metabolic activity, or their environment, based on fluorescence, absorbance and scattering detected. The method may further comprise the step of detecting absorbance.
Another embodiment is directed to a non-invasive method for monitoring skin or tissue constituents in which information about or signature of a specific blood analyte level or disease process is provided comprising the steps of: exciting a target fluorophore; detecting radiation emitted by the fluorophore and transmitted through intervening tissue to the surface; and determining the information or signature from the radiation detected.
As will be clear to those of skill in the art, multiple excitation and emission wavelengths may be used in the various embodiments without departing from the spirit and scope of the invention. For example, multiple excitation wavelengths may be used while doing emission scans. Additionally or alternately, multiple emission wavelengths can be evaluated while doing excitation scans.
Other objects and advantages of the invention are set forth in part in the description which follows and, in part, will be obvious from this description, or may be learned from the practice of the invention.